So far, the main anti-cancer therapeutic strategies have consisted in inhibiting the non-controlled cell proliferation. Nonetheless, as tumour evolution has multifaceted mechanisms, more strategies should be considered in order to address the remaining gaps in cancer management, and more importantly in alleviating the side effects of cancer treatments. Previous research indicates that inflammatory cells and pro-inflammatory molecules mostly contribute to tumor growth and progression. In experimental settings, reduction of inflammatory molecules (e.g. cytokines) inhibits cancer development. Based on earlier research, blockade of inflammation appears to be a relevant strategy for management of cancer. Therefore, controlling or reducing such a process of “malignant flame” (inflammation) represents a crucial approach in the management of cancer.
Anticancer therapies have extended patients' life expectancy; however, cancer-related and its treatment-related comorbidities have become an issue for cancer survivors. The above mentioned disorders are among the most feared side-effects of anticancer agents so that the quality of life (QoL), as well as the life expectancy might be countered by reduced QoL and increased mortality.
Asthenia fatigue syndrome (AFS) or cancer-related fatigue is a common symptom perceived during and after treatment by patients with cancer and consists of pathologic fatigue, poor endurance, and impaired motor and cognitive function. It is a symptom, difficult to define, with a set of vague sensations, different for each patient. Some studies in cancer have reported the findings about how the above-mentioned comorbidities can increase the severity of cancer related fatigue.
A growing body of research has examined the hypothesis that cancer-related fatigue is driven by activation of the pro-inflammatory cytokine network. Actually, inflammation appears to play an essential role in cancer-related fatigue before, during and after cancer therapies. Accordingly, controlling or reducing the persistent inflammatory process can be beneficial to the management of cancer related fatigue. The persistent pathological conditions in cancer patients may favour up-regulated expressions of pro-inflammatory mediators/cytokines and cause a sustained high level of chronic inflammation in the whole body, forming an important ground for triggering the comorbidities of cancer.
In the context of cancer treatment, anti-cancer chemo-agents destroy rapidly dividing cancer cells, as well as all the fast dividing non-cancer cells, which undergo apoptosis due to chemotherapy agents and radiotherapy attack. The massive apoptosis of so many non-cancerous cells results in a large amount of secondary necrotic cells. These necrotic cells will cause and sustain inflammation by stimulating production of pro-inflammatory molecules.
Many internal and external factors can contribute to unwanted prolonged inflammation. However, activated vascular endothelial cells (ECs) in the human vasculature, as they are in direct contact with blood, play pivotal roles in the development of acute and chronic inflammation. Therefore, vascular EC may represent a relevant therapeutic target for the management of cancer and treatment of cancer comorbidities, including but not limited to cancer-related fatigue, cachexia, anorexia, pain, anemia, asthenia, depression, muscle weakness, nausea, vomiting, skin and skin appendages adverse reactions.
One of the possible mechanisms by which inflammation may contribute to the development of tumorgenesis includes enhanced expression of pro-inflammatory mediators such as cytokines (e.g. Interleukin 8) and adhesion molecules, e.g. ICAM-1 (Intercellular Adhesion Molecule 1, also known as CD54), E-selectin/ELAM-1 (also known as CD62E). The adhesion molecules can be found in low concentrations in the membranes of endothelial cells that “line” the interior surface of blood vessels in the whole vascular system. Their expression levels are essential in the inflammatory process. A lower expression of such pro-inflammatory molecules indicates lesser inflammation, while higher expression indicates augmented inflammatory status. Upon toxic or pathological insults, the produced TNF-alpha (Tumor Necrosis Factor) will greatly stimulate expression of adhesion molecules and cytokines exampled by E-selectin, ICAM-1 and Interleukin 8 (IL-8). Increased expressions of adhesion molecules and cytokines mediate immune and inflammatory responses via recruitment of leukocytes to inflammatory sites (infiltration of inflammatory cells through local vascular endothelium).
A former study showed that, compared with controls, the levels of soluble E-selectin and ICAM-1 were significantly higher in breast cancer patients at late stage. Besides, elevated adhesion molecule levels were predictive of decreased survival. In addition, various pro-inflammatory mediators may not only switch on the tumor-prone inflammatory angiogenesis, a process that is essentially controlled by vascular endothelial growth factor, but also promote tumor metastasis. Hence, for reducing harmful inflammation, it is critical to limit the synthesis of these pro-inflammatory molecules so as to decrease the anomalous inflammatory response.
Our studies show that, at molecular level, a composition comprising the ingredients mentioned hereafter is an anti-inflammatory agent, capable of reducing TNFα induced expression of adhesion molecules ICAM-1 and E-selectin on HUVECs (Human Umbilical Vein Endothelial Cells), as well as the cytokine IL-8 expression. Such anti-inflammatory potential results in inhibition of tumour progression and reduction of tumor size (see in the section above and data in the examples, obtained from both in vitro and in vivo studies). Thus, a composition comprising the ingredients mentioned hereafter provides anti-inflammatory effect for the support management of cancer and treatment of cancer comorbidities.
A composition comprising the ingredients mentioned hereafter was subcutaneously injected into a mouse cancer model in a randomized experiment. It was observed that, compared to non-treated mice, the composition inhibits tumor growth and tumor size in treated mice (see data in the example 2 obtained from both in vitro and in vivo studies). A composition comprising the ingredients mentioned hereafter was used in a topical formulation by cancer patients in order to prevent chemotherapy induced alopecia. Some patients reported that, apart from the beneficial effect on unwanted hair loss, other symptoms, such as fatigue, which they were also suffering from, started to improve steadily.